OBJECTIVES: (1) A good correlation exists between elevated levels of specific proteolytic enzymes (notably plasminogen activator) and tumorigenicity in a number of systems. (2) By designing pro-drugs which require activation by plasminogen activator or plasmin and which then act preferentially on proliferating cells (peptidyl derivatives of anticancer drugs), we may narrow the sensitive target population to cells which are both producing the protease and are proliferating. (3) Detailed knowledge of the specificity of plasminogen activators and plasmin can be used to design pro-drugs which give promise of local activation in the vicinity of the tumor. (4) "Self-immolative" connectors can be used to optimize the design of proteolytically activated pro-drugs and thus allow the ideas of the present proposal to be applied to wide classes of drugs.